title: Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis.
abstract: The cysteine protease caspase-8 is an essential executioner of the death receptor (DR) apoptotic pathway. The physiological function of its homologue caspase-10 remains poorly understood, and the ability of caspase-10 to substitute for caspase-8 in the DR apoptotic pathway is still controversial. Here, we analysed the particular contribution of caspase-10 isoforms to DR-mediated apoptosis in neuroblastoma (NB) cells characterised by their resistance to DR signalling. Silencing of caspase-8 in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive NB cells resulted in complete resistance to TRAIL, which could be reverted by overexpression of caspase-10A or -10D. Overexpression experiments in various caspase-8-expressing tumour cells also demonstrated that caspase-10A and -10D isoforms strongly increased TRAIL and FasL sensitivity, whereas caspase-10B or -10G had no effect or were weakly anti-apoptotic. Further investigations revealed that the unique C-terminal end of caspase-10B was responsible for its degradation by the ubiquitin-proteasome pathway and for its lack of pro-apoptotic activity compared with caspase-10A and -10D. These data highlight in several tumour cell types, a differential pro- or anti-apoptotic role for the distinct caspase-10 isoforms in DR signalling, which may be relevant for fine tuning of apoptosis initiation.
authors.affiliation: Department of Paediatrics, Paediatric Oncology Research, University Hospital CHUV, CH-1011 Lausanne, Switzerland. Annick.Muhlethaler@chuv.ch
authors.forename: A
authors.initials: A
authors.lastname: Mühlethaler-Mottet
authors.forename: M
authors.initials: M
authors.lastname: Flahaut
authors.forename: K Balmas
authors.initials: KB
authors.lastname: Bourloud
authors.forename: K
authors.initials: K
authors.lastname: Nardou
authors.forename: A
authors.initials: A
authors.lastname: Coulon
authors.forename: J
authors.initials: J
authors.lastname: Liberman
authors.forename: M
authors.initials: M
authors.lastname: Thome
authors.forename: N
authors.initials: N
authors.lastname: Gross
mesh_terms: D020816:Amino Acid Motifs; D017209:Apoptosis; D053455:Caspase 10 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D053455:Caspase 10; D053181:Caspase 8